Amit Sharma

SENS Foundation · ApotoSENS

Senescent cells can spread the senescent phenotype to other cells by secreting senescence-associated secretory phenotype factors. The resulting paracrine senescent cells make a significant contribution to the burdenofsenescentcellaccumulationwithage.Previouseffortsmadetocharacterizeparacrinesenescence are unreliable due to analyses being based on m...

Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer’s and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious dise...

In the context of aging and age-associated diseases, Natural Killer (NK) cells have been revealed as a key cell type responsible for the immune clearance of senescent cells. Subsequently, NK cell-based therapies have emerged as promising alternatives to drug-based therapeutic interventions for the prevention and treatment of age-related disease and...

Exposure to genotoxic stress by environmental agents or treatments, such as radiation therapy, can diminish healthspan and accelerate aging. We have developed a Drosophila melanogaster model to study the molecular effects of radiation-induced damage and repair. Utilizing a quantitative intestinal permeability assay, we performed an unbiased GWAS sc...

Abstract Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP,...

Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syn- drome, gout and kidney stones. Despite frequent occurrence of these disorders, the genetic pathways influencing UA metabolism and the association with disease remain poorly under- stood. In humans, elevated UA levels resulted from the loss of the of the urate...

Exposure to genotoxic stress by environmental agents or treatments, such as radiation therapy, can diminish health span and accelerate aging. We have developed a Drosophila melanogaster model to study the molecular effects of radiation-induced damage and repair. Utilizing a quantitative intestinal permeability assay, we performed an unbiased GWAS s...

Loss of gut integrity is linked to various human diseases including inflammatory bowel disease. However, the mechanisms that lead to loss of barrier function remain poorly understood. Using D. melanogaster, we demonstrate that dietary restriction (DR) slows the age-related decline in intestinal integrity by enhancing enterocyte cellular fitness thr...

dMyc expression in ECs has an important role for lifespan extension upon dietary restriction. (A and B) Kaplan Meier survival analysis of 5966-GS>dMyc RNAi flies upon AL and DR using the other two different RNAi strains. (C) Kaplan Meier survival analysis of EC-specific dMyc knockdown (using Np-1-Gal4, tub-Gal80ts) upon AL and DR at 29°C. (D) Kapla...

Dietary restriction slows down the incidence of systemic and local infection. (A) Experimental timeline for 5966-GS>dMyc RNAi flies. (B and C) Diptericin (Dpt) mRNA expression in dissected fat bodies (B) and guts (C) from w1118 upon AL and DR was measured with age. mRNA expression from flies at day 0 was set to 1. (D) Age-dependent changes in mRNA...

Inhibition of apoptosis rescues dMyc knockdown mediated gut dysfunction. (A) Smurf gut permeability assay in 5966-GS, dMyc RNAi; + flies and 5966-GS, dMyc RNAi; dronc RNAi 20 days old flies. 5966-GS, dMyc RNAi; + flies–RU486 (AL: n = 61, DR: n = 51), +RU486 (AL: n = 40, DR: n = 70), 5966-GS, dMyc RNAi; dronc RNAi +RU486 (AL: n = 84, DR: n = 77). Er...

Dietary restriction up-regulates dMyc expression in the gut but not other tissues. (A) dMyc mRNA expression in dissected fat bodies from w1118 upon AL and DR was measured with age. mRNA expression from flies at day 0 was set to 1. (B) dMyc mRNA expression in dissected guts from w1118 upon AL and DR was measured with age. dMyc mRNA expression was no...

JNK inhibition failed to rescue dMyc knockdown mediated phenotypes. (A) Acridine orange staining using dissected guts from 30 day old 5966-GS>dMyc RNAi flies. Error bars indicate SEM of 12 guts. (*** p < 0.001 by t-test). (B) puc mRNA expression in dissected guts of 21 day old 5966-GS>dMyc RNAi flies. (C) Lac Z staining of dissected guts from 21 da...

The modest activation of dMyc in EBs/ECs extends health-span on the rich nutrient diets. (A-C) Kaplan-Meier survival analysis of enteroblasts and enterocytes specific dMyc overexpression (5966-GS>UAS-dMyc) upon AL and DR. (A) RU486 was administrated from a day of sorting. (B) RU486 was administrated from day 21 of age. (C) RU486 was administrated e...

Statistical analysis of the survival curves. (DOCX)

EB/EC-specific dMyc knockdown alters gut integrity, but not the expression of septate junction protein. (A) Immunostaining of Discs large (Dlg) using dissected guts from 28 day old 5966-GS>dMyc RNAi flies. Representative image (n = 10). Scale bar indicates 20 μm. (TIF)

Primer sets used for qRT-PCR. (DOCX)

The statistical analysis for EB/EC or ISC/EB-specific dMyc knockdown lifespan. (DOCX)

Summary of the independent repeats of the lifespan analysis. (DOCX)

Elevated uric acid (UA) is a key factor for disorders, including gout or kidney stones and result from abrogated expression of Urate Oxidase (Uro) and diet. To understand the genetic pathways influencing UA metabolism we established a Drosophila melanogaster model with elevated UA using Uro knockdown. Reduced Uro expression resulted in the accumula...

Molecular pathways involved in dauer formation, an alternate larval stage that allows Caenorhabditis elegans to survive adverse environmental conditions during development, also modulate longevity and metabolism. The decision to proceed with reproductive development or undergo diapause depends on food abundance, population density, and temperature....

Aging is known to be the single most important risk factor for multiple diseases. Sirtuin 6, or SIRT6, has recently been identified as a critical regulator of transcription, genome stability, telomere integrity, DNA repair, and metabolic homeostasis. A knockout mouse model of SIRT6 has displayed dramatic phenotypes of accelerated aging. In keeping...

Clinical implications of induced pluripotent stem (iPS) cell technology are enormous for personalized medicine. However, extensive use of viral approach for ectopic expression of reprogramming factors is a major hurdle in realization of its true potential. Non-viral methods for making iPS cells, although plausible, are impractical because of high c...

MicroRNAs (miRs) regulate immunological pathways in health and disease, and a number of miRs have been shown to be altered in mouse models of asthma. The secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine, has been shown to be defective in many inflammatory diseases including asthma. We recently demonstrated that miR-106a inhibits I...

IL-13, a cytokine secreted by T(H)2 lymphocytes and other cells, critically modulates allergic inflammation and tissue remodeling in allergic asthma. Although much is known about transcriptional regulation of IL-13, posttranscriptional regulation is poorly understood. Because many inflammatory pathways are known to be regulated by microRNAs, permit...

Altered arginine metabolism, the uncoupling of nitric oxide synthase (NOS) by asymmetric dimethyl-arginine (ADMA), increased oxo-nitrosative stress, and cellular injury were reported in airway epithelial cells in asthma. Statins improve vascular endothelial dysfunction by reducing ADMA and increasing endothelial NOS (eNOS), thereby reducing oxo-nit...

IL-10 is a key regulator of the immune system that critically determines health and disease. Its expression is finely tuned both at the transcriptional and posttranscriptional levels. Although the importance of posttranscriptional regulation of IL-10 has been previously shown, understanding the underlying mechanisms is still in its infancy. In this...

Piperine displays antipyretic, analgesic, insecticidal and anti-inflammatory activities. It is the first amide to be isolated from Piper species. In the process of identifying non-steroidal anti-inflammatory small molecules from the natural sources, we demonstrate here that piperine inhibits adhesion of neutrophils to endothelial monolayer. The inh...

Isoliquiritigenin (ILTG) is a flavonoid with chalcone structure (4,2',4'-trihydroxychalcone), an active component present in plants like Glycyrrhiza and Dalbergia which showed various biological activities including anti-inflammatory, anti-carcinogenic and antihistamic. As very little is known in regard to the underlying mechanism involved in expla...

Both biochemical and genetic evidence have implicated the genes for TNF-alpha (TNFA) and lymphotoxin-alpha (LTA) in atopic asthma. Here, we report for the first time the association of their genotypes and haplotypes with atopic asthma in Indian populations. We genotyped seven single nucleotide polymorphisms, encompassing the two genes, in patients...